The present invention relates generally to nuclear magnetic resonance (NMR) techniques for both spectroscopy and imaging. More particularly, the present invention relates to the use of hyperpolarized noble gases (e.g., Xe and He) to enhance and improve NMR and MRI.
Nuclear magnetic resonance (NMR) is an established technique for both spectroscopy and imaging. NMR spectroscopy is one of the most powerful methods available for determining primary structure, conformation and local dynamic properties of molecules in liquid, solid and even gas phases. As a whole-body imaging technique, Magnetic Resonance Imaging (MRI) affords images possessing such superb soft tissue resolution that MRI is the modality of choice in many clinical settings. MRI can produce images which allow the clinician to distinguish between a pathological condition and healthy tissue. For example, MR images clearly differentiate tumors from the surrounding tissue. Further, using MRI it is possible to image specific regions within the organism and to obtain anatomical (morphology and pathology) and/or functional information about various processes including blood flow and tissue perfusion. Functional imaging of the brain is now also well documented.
The structural and functional information available through MRI is complemented by whole-body NMR spectroscopy. NMR spectroscopic studies on organisms provides a means to probe the chemical processes occurring in the tissue under study. For example, the location and quantity of intrinsic NMR spectroscopic markers such as lactate and citrate can be studied to gain insight into the chemical processes underlying a disease state (Kurhanewicz, J., et al., Urology 45: 459-466 (1995)). NMR spectroscopy can also be used to observe the effects of administered drugs on the biochemistry of the organism or the changes in the drug which occur following its administration (Maxwell, R. J., Cancer Surv. 17: 415-423 (1993)). Efforts to improve the information yield from MRI and NMR spectroscopy through increased sensitivity or the use of appropriately designed extrinsic probes have been ongoing since the inception of these techniques.
Sensitivity poses a persistent challenge to the use of NMR, both in imaging and spectroscopy. In proton MRI, contrast is primarily governed by the quantity of protons in a tissue and the intrinsic relaxation times of those protons (i.e., T1 and T2). Adjacent tissues which are histologically distinct yet magnetically similar appear isointense on an MR image. As the proton content of a tissue is not a readily manipulable parameter, the approach taken to provide distinction between magnetically similar tissues is the introduction into the biological system of a paramagnetic pharmaceutical (i.e., contrast enhancing agent) such as Gd(DTPA) (Niendorf, H. P., et al., Eur. J. Radiol., 13: 15 (1991)). Interaction between the proton nuclei and the unpaired spins on the Gd+3 ion dramatically decrease the proton relaxation times causing an increase in tissue intensity at the site of interaction. Gd(DJTA) and analogous agents are small molecular agents which remain largely confined to the extracellular compartment and do not readily cross the intact blood-brain barrier. Thus, these agents are of little use in functional brain imaging.
Similar to MRI, NMR spectroscopic studies generally rely on detecting NMR active nuclei which are present in their natural abundance (e.g. 1H, 31P, 13C) (Sapega, A. A., et al., Med. Sci. Sports Exerc., 25: 656-666 (1993)). Additionally, the chemical species under observation must be spectroscopically distinguishable from the other compounds within the window of observation. Thus, sensitivity in NMR spectroscopy is a function of both the abundance and the spectal characteristics of the molecule(s) desired to be studied. The range of NMR spectroscopic studies has been somewhat expanded by the application of exogenous probes which contain NMR active nuclei, for example 19F (Aiken, N. R., et al., Biochim. Biophys. Acta, 1270: 52-57 (1995)).
Noble gases are of interest as tracers and probes for MRI and NMR spectroscopy (Middleton, H., et al., Magn. Res. Med. 33: 271 (1995)), however, the sensitivity of MRI and NMR spectroscopy for these molecules is relatively low. A factor which contributes to the lack of sensitivity of these techniques for the noble gases is that the spin polarization, or net magnetic moment, of the noble gas sample is low. For example, a typical molecule at thermal equilibrium at room temperature has an excess of spins in one direction along an imposed magnetic field relative to those in the opposite direction of generally less than 1 in 105. Lower temperatures and higher fields, to the extent that these can be imposed, provide only limited benefit. Alternative approaches rely on disrupting the equilibrium magnetization by forcing molecules in the sample into a polarized state. Two methods known in the art for enhancing the spin polarization of a population of nuclei are dynamic nuclear polarization and optical pumping.
Dynamic nuclear polarization, originally applied to metals, arises from the cross relaxation between coupled spins. The phenomenon is known as the Overhauser Effect, with early disclosures by Overhauser and others (Ovehauser, A. W., xe2x80x9cPolarization of nuclei in metals,xe2x80x9d Phys. Rev. 92(2): 411-415 (1953), Solomon, I., xe2x80x9cRelaxation processes in a system of two Spins,xe2x80x9d Phys. Rev. 99(2): 559-565 (1955), and Carver, T. R., et al., xe2x80x9cExperimental verification of the Overhauser nuclear polarization effect,xe2x80x9d Phys. Rev. 102(4): 975-980 (1956)). The Nuclear Overhauser Effect between nuclear spins is widely used to determine interatomic distances in NMR studies of molecules in solution.
Optical pumping is a method for enhancing the spin polarization of gases which consists of irradiating an alkali metal, in the presence of a noble gas, with circularly polarized light. The hyperpolarize gases that result have been used for NMR studies of surfaces and imaging void spaces and surfaces. Examples are the enhanced surface NMR of hyperpolarized 129Xe, as described by Raftery, D., et al., Phys. Rev. Lett. 66: 584 (1991); signal enhancement of proton and 13C NMR by thermal mixing from hyperpolarized 129Xe, as described by Driehuys, B., et al., Phys. Lett. A184: 88-92 (1993), and Bowers, C. R., et al., Chem. Phys. Lett. 205: 168 (1993), and by Hartman-Hahn cross-polarization, as described by Long, H. W., et al., J. Am. Chem. Soc. 115: 8491 (1993); and enhanced MRI of void spaces in organisms (such as the lung) and other materials, as described by Albert, M. S., et al., Nature 370: 199-201 (1994), and Song, Y.-Q., et al., J. Magn. Reson. A115: 127-130 (1995).
Although hyperpolarized noble gases have proven useful as probes in the study of the air spaces in lungs, the effectiveness or sensitivity of these methods is somewhat compromised for biological materials and organs, such as blood and the parts of the body that are accessible only through the blood. During its residence time in the blood, the hyperpolarized gas is diluted considerably and the delay in transferring the gas from the lung space to the blood consumes much of the time (e.g., T1) required for the polarized gas to return to its non-hyperpolarized state. Further complicating the situation, the penetration of the hyperpolarized gas into the interior of red blood cells dramatically reduces the T1 of the hyperpolarized gas and thus, sorely attenuates the temporal range over which the gas can serve as an effective probe.
A considerable advance in both MRI and NMR spectroscopy could be achieved by the introduction of a versatile hyperpolarized noble gas-based NMR active tracer which could also function as a contrast enhancing agent or otherwise affect, in a spectroscopically discernable manner, sample molecules to which the probe is proximate. Among other applications, such an agent would be useful in conjunction with functional imaging of the brain and also to probe the dynamics of exchange between the intracellular and extracellular compartments of various tissues. Of even more profound significance would be a means of delivering the tracer, either through the blood or via direct injection into the tissue of interest which maintains the hyperpolarization of the gas during the delivery process and through the imaging or spectroscopic experiment. Quite surprisingly, the instant invention provides both such a tracer and delivery method.
The present invention provides methods for using hyperpolarize noble gases in conjunction with NMR spectroscopy and MRI. The noble gases are useful both as tracers, which are themselves detected, and also as agents which affect the magnetic properties of other nuclei present in a sample.
Thus, in a first aspect, the present invention provides a method for analyzing a sample containing an NMR active nucleus, the method comprising:
(a) contacting the sample with a hyperpolarized noble gas;
(b) scanning the sample by nuclear magnetic resonance spectroscopy, magnetic resonance imaging, or both nuclear magnetic resonance spectroscopy and magnetic resonance imaging;
(c) detecting the NMR active nucleus, wherein the NMR active nucleus is a nucleus other than a noble gas.
In another aspect, the present invention provides a method for analyzing a sample which comprises: (a) combining a hyperpolarized noble gas with a fluid to form a mixture; (b) contacting the sample with the mixture; and (c) scanning the sample, the noble gas or both the sample and the noble gas by nuclear magnetic resonance spectroscopy, magnetic resonance imaging, or both nuclear magnetic resonance spectroscopy and magnetic resonance imaging.
In a further aspect, the invention provides a pharmaceutical composition which comprises a hyperpolarized noble gas dissolved in a physiologically compatible liquid carrier.
In yet another aspect, the present invention provides a method for studying a property of a noble gas in a tissue. This method of the invention comprises: (a) hyperpolarizing a noble gas; (b) dissolving the hyperpolarized noble gas in a physiologically compatible liquid carrier to form a mixture; (c) contacting the tissue with the mixture from (b); and (d) scanning the tissue by nuclear magnetic resonance, magnetic resonance imaging, or both, whereby the property of the noble gas in the tissue is studied.
In a further aspect, the invention provides a method for enhancing the relaxation time of a hyperpolarized noble gas in contact with a physiological fluid. This method comprises: (a) forming a hyperpolarized noble gas intermediate solution by dissolving the hyperpolarized noble gas in a fluid in which the relaxation time of the noble gas is longer than the relaxation time of the noble gas in the physiological fluid; and (b) contacting the physiological fluid with the intermediate solution.
In yet a further aspect, the present invention provides a method for measuring a signal transferred from at least one hyperpolarized noble gas atom to at least one non-noble gas NMR active nucleus, comprising: (a) contacting a non-noble gas NMR active nucleus with a hyperpolarized noble gas atom;
(b) applying radiofrequency energy to the non-noble gas NMR active nucleus in a magnetic field; and (c) measuring the signal transferred from the hyperpolarized noble gas atom to the non-noble gas NMR active nucleus using nuclear magnetic resonance spectroscopy, magnetic resonance imaging, or both.
In a still further aspect, the invention provides a pulse sequence for heteronuclear difference spin polarization induced nuclear Overhauser effect (SPINOE) NMR of a system comprising at least one hyperpolarized noble gas atom and at least one non-noble gas NMR active nucleus, comprising: (a) at least one non-noble gas NMR active nucleus xcfx80/2 pulse; (b) a non-noble gas NMR active nucleus xcfx80 pulse applied simultaneously with application of a noble gas xcfx80 pulse; and (c) a non-noble gas NMR active nucleus xcfx80/2 pulse.
In an additional aspect, the invention provides an apparatus for preparing a solution of a hyperpolarized noble gas in a fluid, the apparatus comprising:
a vessel for receiving the fluid;
a reservoir for receiving the hyperpolarized noble gas, the reservoir communicating through a first shutoff valve with the vessel, the reservoir being shaped to allow the reservoir to be cooled independently of the vessel;
a gas inlet port communicating through a second shutoff valve with the reservoir; and
a means for withdrawing the fluid from the vessel independently of the first and second shutoff valve.
Other features, objects and advantages of the invention and its preferred embodiments will become apparent from the detailed description which follows.